Stearoyl-CoA Desaturase 1 Protects Ovarian Cancer Cells from Ferroptotic Cell Death

Abstract

Activation of ferroptosis, a recently described mechanism of regulated cell death, dramatically inhibits growth of ovarian cancer cells. Given the importance of lipid metabolism in ferroptosis and the key role of lipids in ovarian cancer, we examined the contribution to ferroptosis of steroyl CoA desaturase (SCD1), an enzyme that catalyzes the rate-limiting step in monounsaturated fatty acid synthesis, in ovarian cancer cells. SCD1 was highly expressed in ovarian cancer tissue, cell lines, and a genetic model of ovarian cancer stem cells. Inhibition of SCD1 induced lipid oxidation and cell death. Conversely, over-expression of SCD1 or exogenous administration of its C16:1 and C18:1 products, palmitoleic acid or oleate, protected cells from death. Inhibition of SCD1 induced both ferroptosis and apoptosis: inhibition of SCD1 decreased CoQ 10 , an endogenous membrane antioxidant whose depletion has been linked to ferroptosis, while concomitantly decreasing unsaturated fatty acyl chains in membrane phospholipids and increasing long chain saturated ceramides, changes previously linked to apoptosis. Simultaneous triggering of two death pathways suggests SCD1 inhibition may be an effective component of anti-tumor therapy, since overcoming this dual mechanism of cell death may present a significant barrier to the emergence of drug resistance. Supporting this concept, we observed that inhibition of SCD1 significantly potentiated the anti-tumor effect of ferroptosis inducers in both ovarian cancer cell lines and a mouse orthotopic xenograft model. Our results suggest that the use of combined treatment with SCD1

Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases

“…This fact points out that SCD1 is a central element of lipid metabolism and body weight control [14]. Interestingly, its deficiency is also associated with a narrow eye fissure [22] and skin abnormalities [17]. Recently, it has been demonstrated that SCD1 protects against the palmitate-induced cytotoxic effect in mesenchymal stromal cells and osteoblasts [23].…”

“…Cancer stem cells (CSCs) are usually associated with chemoresistance and cancer. High levels of SCD1 have also been observed in CSCs [17,31,45,67,68]. In lung tumor spheroids, SCD1 expression was significantly upregulated [67] and SCD1 inhibition with MF-438 reverts tumoral cisplatin resistance [45,69].…”

“…SCD1 is located in the ER of cells in many tissues (lung, pancreas, skeletal muscle, brain, adipose tissue) while SCD5 is only located in brain and pancreas [14][15][16]. Although a compensatory effect was observed in some breast cancer models, SCD5 [8] is not able to restore the effects of SCD1 deficiency [17]. Recently, it has been described that SCD5 is also expressed in the fetal brain of dogs, bovines, and birds [18].…”

“…Many SCD1 inhibitors have been tested with good results in liver diseases such as nonalcoholic fatty liver, diabetes, dyslipidemic failure, and hepatitis C virus (HCV) infections [17]. For example, MK-8245 is right now in advanced phase 2 human clinical studies [14] (Table 1).…”

The epigenetic regulators and metabolic changes in ferroptosis-associated cancer progression

“…With the help of EGLNs, an enzyme that contributes to the degradation of HIF-1α, c-Myc is recruited to the LSH gene promoter, upregulating LSH expression [86,130]. Another group also reports that SCD1, an enzyme that catalyzes the rate-limiting step in monounsaturated fatty acid synthesis, inhibits ferroptosis through increasing CoQ10 (Coenzyme Q-binding protein 10), an endogenous membrane antioxidant whose depletion has been linked to ferroptosis [131].…”